The present invention concerns tetrahydro xcex3-carbolines having a broad therapeutic potential. It further relates to their preparation, compositions comprising them and their use as a medicine.
U.S. Pat. No. 4,636,563, published on Jan. 13, 1987, and U.S. Pat. No. 4,672,117, published on Jun. 9, 1987, disclose 2-(heteroaryl-alkyl)-tetrahydro-xcex3 carbolines having antipsychotic activity. EP-A-0,705,832, published on Apr. 10, 1996, discloses 1,2,3,4-terahydro-9H-pyrido3,4-b]indolyl-alkyl-1,3-dihydro-2H-benzimidazolones as serotonergic modulators.
The compounds of the present invention are novel and have an interesting broad-spectrum receptor-binding profile. In comparison to the structurally related known compounds, they surprisingly exhibit a greater therapeutic breadth.
The present invention concerns the compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein:
R1 is hydrogen, C1-6alkyl, aryl or C1-6alkyl substituted with aryl;
R2 is each independently a halogen, hydroxy, C1-6alkyl, C1-6alkyloxy or nitro;
n is 0, 1, 2 or 3;
Alk is C1-6alkanediyl;
D is 2(3H)benzoxazolone-3-yl or a radical of formula 
xe2x80x83wherein
each X independently represents O, S or NR12;
R3 is hydrogen, C1-6alkyl, aryl or arylC1-6alkyl;
R4 is hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono- or di(C1-6alkyl)amino or mono- or di(arylC1-6alkyl)amino;
R5, R6, R7, R10, R11 and R12 each independently are hydrogen or C1-6alkyl;
R8 and R9 each independently are hydrogen, C1-6alkyl or aryl; or
R4 and R5 taken together may form a bivalent radical xe2x80x94R4xe2x80x94R5xe2x80x94 of formula 
xe2x80x83wherein one or two hydrogen atoms of said radicals (a-1) to (a-5) each independently may be replaced by halogen, C1-6alkyl, arylC1-6alkyl, trifluoromethyl, amino, hydroxy, C1-6alkyloxy or C1-6alkylcarbonyloxy; or where possible, two geminal hydrogen atoms may be replaced by C1-6alkylidene or arylC1-6alkylidene; or
xe2x80x94R4xe2x80x94R5xe2x80x94 may also be 
xe2x80x83wherein one or where possible two or three hydrogen atoms in said radicals (a-6) to (a-14) each independently may be replaced by C1-6alkyl or aryl; and
aryl is phenyl or phenyl substituted with a halogen or C1-6alkyl.
As used in the foregoing definitions the term halogen is generic to fluoro, chloro, bromo and iodo. The term C1-4alkyl defines straight and branched saturated hydrocarbons, having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl and the like. The term C1-6alkyl is meant to include C1-6alkyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pentyl, hexyl or the like. The term C1-10alkyl is meant to include C1-6alkyl radicals and the higher homologues thereof having 7 to 10 carbon atoms such as, for example, heptyl, octyl, nonyl, decyl and the like. The term C1-4alkanediyl defines bivalent straight or branch chained alkanediyl radicals having from 1 to 4 carbon atoms such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like; the term C1-6alkanediyl is meant to include C1-4alkanediyl and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, 1,5-pentanediyl, 1,6-hexanediyl and the like; the term C1-6alkylidene defines bivalent straight or branch chained alkylidene radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethylidene, 1-propylidene, 1-butylidene, 1-pentylidene, 1-hexylidene and the like.
Also as used hereinafter, the term benzyl refers to phenylmethyl. Other names for the term xcex3-carboline are 5H-pyrido[4,3-b]indole, 3-azacarbazole and 3-azarbazole.
The addition salts as mentioned herein are meant to comprise the therapeutically active addition salt forms which the compounds of formula (I) are able to form with appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
The pharmaceutically acceptable addition salts as mentioned hereinabove are also meant to comprise the therapeutically active non-toxic base, in particular, a metal or amine addition salt forms which the compounds of formula (I) are able to form. Said salts can conveniently be obtained by treating the compounds of formula (I) containing acidic hydrogen atoms with appropriate organic and inorganic bases such as, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
Conversely said salt forms can be converted by treatment with an appropriate base or acid into the free acid or base form.
The term addition salt as used hereinabove also comprises the solvates which the compounds of formula (I) are able to form and said solvates are meant to be included within the scope of the present invention. Examples of such solvates are, e.g. the hydrates, alcoholates and the like.
The N-oxide forms of the compounds of formula (I) are meant to comprise those compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
The term stereochemically isomeric forms as used herein defines all the possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure.
Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
Whenever used hereinafter, the term compounds of formula (I) is meant to include also the N-oxide forms, the pharmaceutically acceptable addition salts and all stereoisomeric forms.
A special group of compounds includes those compounds of formula (I) wherein one or more of the following restrictions apply:
1) R2 is halogen, hydroxy, C1-6alkyl or C1-6alkyloxy;
2) n is 0 or 1;
3) Alk is C1-4alkanediyl; preferably, Alk is 1,2-ethanediyl;
4) D is a radical of formula (a) wherein R3 is C1-6alkyl, aryl or arylC1-6alkyl; R4 is amino, mono- or di(C1-6alkyl)amino, or mono- or di(arylC1-6alkyl)amino; or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-2) or (a-5) wherein one or two hydrogen atoms each independently may be replaced by halogen, C1-6alkyl, trifluoromethyl or C1-6alkyloxy, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-6), (a-7), (a-8), (a-11), (a-13) or (a-14) wherein one or where possible two hydrogen atoms each independently may be replaced by C1-6alkyl;
5) D is a radical of formula (b) and R6 and R7 are suitably methyl;
6) D is a radical of formula (c) and R8 is suitably hydrogen, methyl or phenyl;
7) D is a radical of formula (d) wherein R9 is aryl; and suitably, R9 is 4-fluoro-phenyl, and the piperidine ring is connected in the 3- or 4-position to the remainder of the molecule;
8) D is a radical of formula (e) wherein X is S or NH and R10 is hydrogen; or
9) D is a radical of formula (f) wherein X is S or NCH3.
In case n is 1, the R2 substituent is suitably positioned in the 6-, 7- or 8-position of the xcex3-carboline moiety, preferably in the 7- or 8-position, and R2 is preferably chloro, fluoro, methyl, hydroxy or methoxy.
Suitably, D is a radical of formula (a), (d), (e) or (f).
An interesting group of compounds includes those compounds of formula (I) wherein R1 is hydrogen or aryl; R2 is halogen or C1-6alkyl; n is 0 or 1; Alk is C1-4alkanediyl; D is a radical of formula (a) or (e), especially a radical of formula (a) wherein R3 is C1-6alkyl and xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-2), (a-5), (a-6), (a-7) or (a-8) wherein one or where possible two hydrogen atoms each independently may be replaced by C1-6alkyl, or a radical of formula (e) wherein X is S and R10 is hydrogen.
Another interesting group of compounds includes those compounds of formula (I) wherein R1 is hydrogen or C1-6alkyl; R2 is halogen, C1-6alkyl or C1-6alkyloxy; n is 0 or 1; Alk is C1-4alkanediyl; D is a radical of formula (a) or (f), especially a radical of formula (a) wherein R4 is amino, mono- or di(C1-6alkyl)amino or mono- or di(arylC1-6alkyl)amino, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-2), (a-5), (a-6), (a-7), (a-8) or (a-11) wherein one or where possible two hydrogen atoms each independently may be replaced by C1-6alkyl or a radical of formula (f) wherein X is NR12.
Yet another interesting group of compounds includes those compounds of formula (I) wherein R2 is halogen, hydroxy, C1-6alkyl or C1-6alkyloxy; n is 0 or 1, Alk is C1-4alkanediyl; D is a radical of formula (a), (e) or (f), especially a radical of formula (a) wherein R3 is C1-6alkyl, R4 is amino, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-2) or (a-5) wherein one or two hydrogen atoms each independently may be replaced by halogen, C1-6alkyl, trifluoromethyl or C1-6alkyloxy, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-6), (a-7), (a-8), (a-11), (a-13) or (a-14) wherein one or where possible two hydrogen atoms each independently may be replaced by C1-6alkyl, or a radical of formula (e) wherein X is S or NR12 and R10 is hydrogen, or a radical of formula (f) wherein X is S or NR12.
Still another interesting group of compounds includes those compounds of formula (I) wherein R1 is hydrogen, C1-6alkyl or aryl; R2 is halogen, C1-6alkyl or C1-6alkyloxy; n is 0 or 1; Alk is C1-4alkanediyl; D is a radical of formula (a), (d) or (e), especially a radical of formula (a) wherein R3 is C1-6alkyl or arylC1-6alkyl, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-5) wherein one or two hydrogen atoms each independently may be replaced by a halogen, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-6) or (a-8), or a radical of formula (d) wherein R9 is aryl, or a radical of formula (e) wherein X is S or NR12 and R10 is hydrogen.
Particular compounds are those compounds of formula (I) wherein R1 is hydrogen; n is 0 or n is 1 whereby R2 is a halogen, C1-6alkyl, or C1-6alkoxy; Alk is 1,2-ethanediyl and D is a radical of formula (a) or (f), especially a radical of formula (a) wherein R3 is C1-6alkyl, R4 is amino, R5 is C1-6alkyl, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-2), (a-5), (a-6), (a-7), (a-8) or (a-11) wherein one hydrogen atom may be replaced by C1-6alkyl, or a radical of formula (f) wherein X is NR12 and R11 is C1-6alkyl; more in particular, wherein R1 is hydrogen; n is 0 or n is 1 whereby R2 is a chloro, methyl, or methoxy; Alk is 1,2-ethanediyl and D is a radical of formula (a) wherein R3 is methyl, R4 is amino, R5 is methyl, or xe2x80x94R4xe2x80x94R5xe2x80x94 is a radical of formula (a-2), (a-5), (a-6), (a-7), (a-8) or (a-11) wherein one hydrogen atom may be replaced by methyl, or D is a radical of formula (f) wherein X is Nxe2x80x94CH3 and R11 is methyl.
Other particularly interesting compounds are those compounds of formula (I) wherein R1 is hydrogen; n is 0 or n is 1 whereby R2 is a halogen or C1-6alkyl; Alk is 1,2-ethanediyl and D is a radical of formula (a), especially a radical of formula (a) wherein R3 is C1-6alkyl, R4 and R5 are taken together to form xe2x80x94R4xe2x80x94R5xe2x80x94 of formula (a-2), (a-5), (a-6), (a-7) or (a-8) wherein one hydrogen atom may be replaced by C1-6alkyl; more in particular, wherein R1 is hydrogen; n is 0 or n is 1 whereby R2 is a chloro, fluoro or methyl; Alk is 1,2-ethanediyl and D is a radical of formula (a) wherein R3 is methyl, R4 and R5 are taken together to form xe2x80x94R4xe2x80x94R5xe2x80x94 of formula (a-2), (a-5), (a-6), (a-7) or (a-8) wherein one hydrogen atom may be replaced by methyl.
A preferred set of compounds includes those compounds of formula (I) wherein R1 is hydrogen, methyl, n-butyl, phenyl, benzyl or 4-fluoro-phenyl.
The compounds of formula (I) can generally be prepared by N-alkylating a 1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indole derivative of formula (II) with an alkylating reagent of formula (III) following the procedure described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255. 
In particular, intermediate (II) wherein W1 represents an appropriate reactive leaving group such as, for example, a halogen, e.g. chloro, bromo or iodo; a sulfonyloxy, e.g. methanesulfonyloxy, toluenesulfonyloxy, may be reacted with an intermediate of formula (II) in a reaction-inert solvent such as, for example, N,N-dimethylformamide or methylisobutylketon, in the presence of a suitable base such as, for example, sodiumcarbonate or triethylamine, and optionally in the presence of a catalyst such as, for example, potassium iodide.
In this and the following reactions, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as extraction, crystallization, trituration and chromatography.
The compounds of formula (I) wherein D is a radical of formula (e), being represented by formula (I-e), may be prepared by N-acylating an intermediate of formula (IV) with an acyl derivative of formula (V) wherein W2 is an appropriate reactive leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, chloroform, in the presence of a suitable base such as, for example, sodium carbonate or triethylamine. 
The compounds of formula (I) wherein D is a radical of formula (f), being represented by formula (I-f), can be prepared by N-alkylating an amine of formula (VI) with an intermediate of formula (VII) wherein W3 is an appropriate reactive leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, ethanol or toluene, in the presence of a suitable base such as, for example, sodiumbicarbonate or sodiumcarbonate. 
Alternatively, intermediates (VI) may be N-alkylated with intermediates (VII) in the presence of copper.
The compounds of formula (I) may be converted into each other following art-known functional group transformation reactions.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
A number of intermediates and starting materials are commercially available or are known compounds which may be prepared according to art-known methodologies.
For example, some of the intermediates of formula (III) and their preparations are described in EP-A-0,037,265, EP-A-0,070,053, EP-A-0,196,132 and in EP-A-0,378,255.
Intermediates of formula (II) wherein R1 is hydrogen, said intermediates being represented by formula (II-a), can generally be prepared by reacting an intermediate of formula (VIII) wherein P is a protective group such as, for example, an alkyloxycarbonyl group, with an intermediate of formula (IX) in a reaction-inert solvent, thus forming an intermediate of formula (X), and subsequently removing the protective group using art-known techniques such as, for instance, mixing the intermediate of formula (X) with potassium hydroxide in 2-propanol. Alternatively, the intermediate of formula (X) may be further reacted with a reagent of formula (XI) wherein R1xe2x80x2 is the same as R1 but other than hydrogen and W4 is a suitable leaving group such as, for example, a halogen, in a suitable solvent such as, for example, hexamethylphosphorous triamide and the like, in the presence of an appropriate base such as, for example, sodium hydride, thus forming an intermediate of formula (XII) which may subsequently be deprotected using art-known techniques resulting in a compound of formula (II) wherein R1 is other than hydrogen, said compounds being represented by formula (II-b). 
Intermediates of formula (IV) can be prepared by N-alkylating an intermediate of formula (II) with an intermediate of formula (XIII) wherein P is a protective group such as, for example, an alkyloxycarbonyl group, and W5 is a suitable leaving group such as, for example, a p-toluenesulfonyloxy group and the like, in a reaction-inert solvent such as, for example, N,N-dimethylformamide, and in the presence of a suitable base such as, for example, sodium carbonate. The thus formed intermediate may be deprotected using art-known deprotection techniques. 
Intermediates of formula (VI) may be prepared by N-alkylating an intermediate of formula (II) with an intermediate of formula (XIV) wherein P is a protective group such as, for example, an alkyloxycarbonyl group, and W6 is a suitable leaving group such as, for example, a halogen, in a reaction-inert solvent such as, for example, methylisobutylketon, in the presence of a suitable base such as, for example, sodium carbonate, and optionally in the presence of a catalyst such as, for instance, potassium iodide. The thus formed intermediate may be deprotected using art-known deprotection techniques. 
Intermediates of formula (VI) wherein Alk is 1,3-propanediyl and R11 is hydrogen, said intermediates being represented by formula (VI-3) may suitably be prepared by reacting an intermediate of formula (II) with acrylonitrile in a reaction-inert solvent such as, for example, 2-propanol, and in the presence of a suitable catalyst such as, for example, a quaternary ammonium compound, e.g. Aliquat 336, thus forming a nitrile derivative of formula (XV) which may subsequently be reduced to the corresponding amine derivative using art-known reduction techniques as there are, for example, the use of hydrogen with Raney Nickel as a catalyst in methanol, optionally in the presence of ammonia. 
Intermediates of formula (VI) wherein Alk is 1,4-butanediyl and R11 is hydrogen, said intermediates being represented by formula (VI-4) may suitably be prepared by reacting an intermediate of formula (II) with an intermediate of formula (XVI) wherein W7 is a suitable leaving group such as, for example a halogen, in a reaction-inert solvent such as, for example, methylisobutylketon, and in the presence of a suitable base such as, for example, sodium carbonate, and optionally in the presence of a catalyst such as, for instance, potassium iodide, thus forming a nitrile derivative of formula (XVII) which may subsequently be reduced to the corresponding amine derivative using art-known reduction techniques as there are, for example, the use of hydrogen with Raney Nickel as a catalyst in methanol, optionally in the presence of ammonia. 
Some of the compounds of formula (I) and some of the intermediates in the present invention contain at least one asymmetric carbon atom. Pure stereochemically isomeric forms of said compounds and said intermediates can be obtained by the application of art-known procedures. For example, diastereoisomers can be separated by physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by first converting said racemic mixtures with suitable resolving agents such as, for example, chiral acids, to mixtures of diastereomeric salts or compounds; then physically separating said mixtures of diastereomeric salts or compounds by, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting said separated diastereomeric salts or compounds into the corresponding enantiomers.
Pure stereochemically isomeric forms of the compounds of formula (I) may also be obtained from the pure stereochemically isomeric forms of the appropriate intermediates and starting materials, provided that the intervening reactions occur stereospecifically. The pure and mixed stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of the present invention.
The compounds of formula (I), their pharmaceutically acceptable addition salts, stereochemically isomeric forms, or N-oxide forms thereof, all show a particular affinity for serotonin receptors, such as, 5-hydroxytryptamine receptors of the 5HT1- and 5-HT2-type, and have an antagonistic, partially antagonistic or agonistic effect thereon. Apart from their serotonergic receptor affinity, the present compounds also bind as ligands on the xcex12- or dopamine receptors, or selectively inhibit serotonin reuptake. This broad-spectrum receptor-binding profile of the present compounds gives them a great therapeutic breadth. They are useful in controlling diseases which are characterized by disturbances of the serotonergic system, in particular with involvement of 5HT2-type receptors. They are therefore suitable for treating disorders of the central nervous system including psychotic disorders such as, e.g. schizophrenia, tension and depression states, neuroses, psychoses, bipolar disorders, aggressive behaviour, anxiety and the like. Further, serotonin is a potent broncho- and vasoconstrictor and thus the present compounds acting as antagonists on the serotonin receptors may also be used against hypertension and vascular disorders such as, migraine and migraine related disorders. Compounds controlling the serotonergic system have been associated with a number of other properties such as, the suppression of appetite and promotion of weight loss, which may prove effective in combatting obesity; the alleviation of withdrawal symptoms in addicts trying to discontinue drinking and smoking habits; and also with gastrointestinal disorders such as, e.g. colonkinetic disturbances.
Also the inhibitory activity of a particular group of the present compounds on the reuptake of serotonin contributes to the effectiveness to treat tension and depression states.
An additional feature of the present compounds is that they have central xcex12-adrenoceptor antagonistic activity. Central xcex12-adrenoceptor antagonists are known to increase noradrenaline release by blocking presynaptic xcex12-receptors which exert an inhibiting control over the release of the neurotransmitter. By increasing the noradrenaline concentrations, xcex12-antagonists can be used particularly for the treatment or prophylaxis of depression, and are also potentially useful in the treatment of Alzheimer""s disease and dementia as it is known that xcex12-antagonists promote the release of acetylcholine (Tellez et al. 1997, J. Neurochem. 68:778-785).
A particular group of the present compounds exhibits. a pronounced affinity for dopaminergic receptors which in combination with an affinity for serotonergic receptors is of therapeutic significance in the treatment of psychosis.
The 5-HT2 receptor-binding profile of the compounds of formula (I) is discussed in the pharmacological example C.1. The binding profile for other recptors such as, the xcex12-adrenergic or the dopaminergic receptors, may be demonstrated using analogous radioligand binding studies. Further, the serotonergic properties of the present compounds may be evidenced by the xe2x80x9capomorphine, tryptamine, norepinephrine (ATN) test in ratsxe2x80x9d, described in Arch. Int. Pharmacodyn., 227, 238-253 (1977).
The present invention thus relates to compounds of formula (I) as defined hereinabove for use as a medicine. Also, the present invention relates to the use of the present compounds for the manufacture of a medicament for treating depression, anxiety and psychosis.
In view of the usefulness of the subject compounds in the treatment or prevention of the above-mentioned disorders, the present invention provides a method of treating warm-blooded animals suffering from such disorders, in particular depression, anxiety and psychosis, said method comprising the systemic administration of a therapeutic effective amount of a compound of formula (I), a N-oxide or a pharmaceutically acceptable addition salt thereof, effective in treating disorders associated with the serotonergic system
In general it is contemplated that an effective therapeutic daily amount would be from about 0.01 mg/kg to about 4 mg/kg body weight. The exact dosage to be used in the treatment of any of the above-mentioned disorders must be subjectively determined by the attending physician. The variables involved include the severity of the disorder and the size, age and response pattern of the patient.
For administration purposes, the subject compounds may be formulated into various pharmaceutical compositions comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, in addition salt or in free acid or base form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable solutions containing compounds of formula (I) may be formulated in an oil for prolonged action. Appropriate oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soy bean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wettable agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause any significant deleterious effects on the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on or as an ointment. Addition salts of (I) due to their increased water solubility over the corresponding free base or free acid form, are obviously more suitable in the preparation of aqueous compositions.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.